Novel Pyrazole-Chalcone Hybrids: Synthesis and Computational Insights Against Breast Cancer.

More women die of breast cancer than of any other malignancy. The resistance and toxicity of traditional hormone therapy created an urgent need for potential molecules for treating breast cancer effectively. Novel biphenyl-substituted pyrazole chalcones linked to a pyrrolidine ring were designed by using a hybridization approach. The hybrids were assessed against MCF-7 and MDA-MB-231 cells by NRU assay. Among them, 8 k, 8 d, 8 m, 8 h, and 8 f showed significantly potent IC50 values: 0.17, 5.48, 8.13, 20.51, and 23.61 µM) respectively, on MCF-7 cells compared to the positive control Raloxifene and Tamoxifen. Furthermore, most active compound 8 k [3-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(2-(2-(pyrrolidin-1-yl)-ethoxy)-phenyl)-chalcone] showed cell death induced through apoptosis, cell cycle arrest at the G2/M phase, and demonstrated decrease of ER-α protein in western blotting study. Docking studies of 8 k and 8 d established adequate interactions with estrogen receptor-α as required for SERM binding. The active hybrids exhibited good pharmacokinetic properties for oral bioavailability and drug-likeness. Whereas, RMSD, RMSF, and Rg values from Molecular dynamics studies stipulated stability of the complex formed between compound 8 k and receptor. All of these findings strongly indicate the antiproliferative potential of pyrazole-chalcone hybrids for the treatment of breast cancer.

Discovery of Novel Pyrimidine Based Small Molecule Inhibitors as VEGFR-2 Inhibitors: Design, Synthesis, and Anti-Cancer Studies.

BACKGROUND: Receptor tyrosine kinases (RTKs) are potent oncoproteins in cancer that, when mutated or overexpressed, can cause uncontrolled growth of cells, angiogenesis, and metastasis, making them significant targets for cancer treatment. Vascular endothelial growth factor receptor 2 (VEGFR2), is a tyrosine kinase receptor that is produced in endothelial cells and is the most crucial regulator of angiogenic factors involved in tumor angiogenesis. So, a series of new substituted N-(4-((2-aminopyrimidin-5-yl)oxy)phenyl)-N-phenyl cyclopropane1,1-dicarboxamide derivatives as VEGFR-2 inhibitors have been designed and synthesized. METHODS: Utilizing H-NMR, C13-NMR, and mass spectroscopy, the proposed derivatives were produced and assessed. HT-29 and COLO-205 cell lines were used for the cytotoxicity tests. The effective compound was investigated further for the Vegfr-2 kinase inhibition assay, cell cycle arrest, and apoptosis. A molecular docking examination was also carried out with the Maestro-12.5v of Schrodinger. RESULTS: In comparison to the reference drug Cabozantinib (IC50 = 9.10 and 10.66 µM), compound SP2 revealed promising cytotoxic activity (IC50 = 4.07 and 4.98 µM) against HT-29 and COLO-205, respectively. The synthesized compound SP2 showed VEGFR-2 kinase inhibition activity with (IC50 = 6.82 µM) against the reference drug, Cabozantinib (IC50 = 0.045 µM). Moreover, compound SP2 strongly induced apoptosis by arresting the cell cycle in the G1 phase. The new compounds' potent VEGFR-2 inhibitory effect was noted with key amino acids Asp1044, and Glu883, and the hydrophobic interaction was also observed in the pocket of the VEGFR-2 active site by using a docking study. CONCLUSION: The results demonstrate that at the cellular and enzyme levels, the synthetic compounds SP2 are similarly effective as cabozantinib. The cell cycle and apoptosis data demonstrate the effectiveness of the suggested compounds. Based on the findings of docking studies, cytotoxic effects, in vitro VEGFR-2 inhibition, apoptosis, and cell cycle arrest, this research has given us identical or more effective VEGFR-2 inhibitors.

Emerging perspectives: unraveling the anticancer potential of vitamin D3.

Vitamin D3, a fat-soluble vitamin known for its critical function in calcium homeostasis and bone health, is gaining interest for its anticancer properties. Observational studies have suggested a negative relationship between vitamin D levels and the incidence of some malignancies throughout the years, prompting substantial investigation to find its anticancer effects. The purpose of this comprehensive review is to investigate the diverse function of vitamin D3 in cancer prevention and therapy. We explored the molecular mechanism underlying its effects on cancer cells, which range from cell cycle control and death to angiogenesis and immune response modulation. Insights from in vitro and in vivo studies provide valuable evidence supporting its anticancer potential. Furthermore, we look at epidemiological and clinical studies that investigate the relationship between vitamin D3 levels and cancer risk or treatment results. Vitamin D3 supplementation's safety profile and cost-effectiveness increase its attractiveness as an adjuvant therapy in conjunction with traditional treatment regimens. Our critical review of the current literature provides an in-depth understanding of vitamin D3's anticancer effect, covering the obstacles and possibilities in realizing its promise for cancer prevention and therapy. The findings of this study might pave the way for the development of innovative treatment techniques that take use of the advantages of vitamin D3 to fight cancer and improve patient care. As research progresses, a better understanding of vitamin D3's anticancer processes will surely simplify its incorporation into personalized cancer care techniques, hence enhancing patient outcomes in the battle against cancer.

Discovery of New Quinazoline Derivatives as VEGFR-2 Inhibitors: Design, Synthesis, and Anti-proliferative Studies.

BACKGROUND: In cancer, Receptor tyrosine kinases (RTKs) are powerful oncoproteins that can lead to uncontrolled cell proliferation, angiogenesis, and metastasis when mutated or overexpressed, making them crucial targets for cancer treatment. In endothelial cells, one of them is vascular endothelial growth factor receptor 2 (VEGFR2), a tyrosine kinase receptor that is produced and is the most essential regulator of angiogenic factors involved in tumor angiogenesis. So, a series of new N-(4-(4-amino-6,7-dimethoxyquinazolin-2-yloxy)phenyl)-N-phenyl cyclopropane-1,1- dicarboxamide derivatives as VEGFR-2 inhibitors have been designed and synthesized. METHODS: The designed derivatives were synthesized and evaluated using H-NMR, C13-NMR, and Mass spectroscopy. The cytotoxicity was done with HT-29 and COLO-205 cell lines. The potent compound was further studied for Vegfr- 2 kinase inhibition assay. Furthermore, the highest activity compound was tested for cell cycle arrest and apoptosis. The molecular docking investigation was also done with the help of the Glide-7.6 program interfaced with Maestro- 11.3 of Schrodinger 2017. The molecular dynamics simulation was performed on the Desmond module of Schrodinger. RESULTS: Compound SQ2 was observed to have promising cytotoxic activity (IC50 = 3.38 and 10.55 µM) in comparison to the reference drug Cabozantinib (IC50 = 9.10 and 10.66 µM) against HT-29 and COLO-205, respectively. The synthesized compound SQ2 showed VEGFR-2 kinase inhibition activity (IC50 = 0.014 µM) compared to the reference drug, Cabozantinib (IC50 = 0.0045 µM). Moreover, compound SQ2 strongly induced apoptosis by arresting the cell cycle in the G1 and G2/M phases. The docking study was performed to understand the binding pattern of the new compounds to the VEGFR-2 active site. Docking results attributed the potent VEGFR-2 inhibitory effect of the new compounds as they bound to the key amino acids in the active site, Asp1044, and Glu883, as well as their hydrophobic interaction with the receptor's hydrophobic pocket. The advanced computational study was also done with the help of molecular dynamics simulation. CONCLUSION: The findings show that the developed derivatives SQ2 and SQ4 are equally powerful as cabozantinib at cellular and enzymatic levels. The apoptosis and cell cycle results show that the proposed compounds are potent. This research has provided us with identical or more potent VEGFR-2 inhibitors supported by the results of docking studies, molecular dynamics simulation, cytotoxic actions, in vitro VEGFR-2 inhibition, apoptosis, and cell cycle arrest.

Recent progress in targeting KRAS mutant cancers with covalent G12C-specific inhibitors.

KRASG12C has been identified as a potential target in the treatment of solid tumors. One of the most often transformed proteins in human cancers is the small Kirsten rat sarcoma homolog (KRAS) subunit of GTPase, which is typically the oncogene driver. KRASG12C is altered to keep the protein in an active GTP-binding form. KRAS has long been considered an 'undrugable' target, but sustained research efforts focusing on the KRASG12C mutant cysteine have achieved promising results. For example, the US Food and Drug Administration (FDA) has passed emergency approval for sotorasib and adagrasib for the treatment of metastatic lung cancer. Such achievements have sparked several original approaches to KRASG12C. In this review, we focus on the design, development, and history of KRASG12C inhibitors.

Design, Synthesis, Molecular Docking, and Preliminary Pharmacological Screening of some New Benzo[d]thiazol-2-ylamino Containing Chromen-2- one Derivatives with Atypical Antipsychotic Profile.

INTRODUCTION: Mental disorders are very serious complicated disorders. Schizophrenia is one of the most baffling mental disorders. The new series 7-(2-(benzo[d]thiazol-2- ylamino)ethoxy)-4-methyl-2H-chromen-2- synthesized in search of newer compounds for Schizophrenia. METHODS: Synthesis is done by refluxing in dry pyridine with various substituted 2-amino benzothiazoles derivatives (3a-3k) and 7-(2-Chloroethoxy)-4-methyl-2H-chromen-2-one (2). The molecular docking approach was used to screen these generated derivatives. Chem Bio Draw Ultra 12 was used to draw the compounds, which were then exposed to all potential conformations of compounds interacting with receptors. The Glide 7.6, Schrodinger 2017 Maestro 11.3 was used to achieve molecular docking. The Dopamine receptor 6CM4 serotonin 5TUD PDBs were acquired from the database of Brookhaven Protein. Using the OPLS 2005 force field, the ligand-protein hydrogen-bond network was acquired, along with the overall energy reduced. A glide score was used to rate the docking poses. RESULTS: The produced compounds have been identified with the use of analytical and spectral data. All of the produced substances were tested and analyzed for serotonin 5HT2 antagonistic and dopamine D2 activity, which can be considered as a measure of typical antipsychotic properties. CONCLUSION: Compounds 4b, 4c, 4e, 4g & 4i have demonstrated promising pharmacological action in preliminary studies. According to the preceding findings, compounds with electronwithdrawing substitutions, such as 4e & 4b, have a good atypical profile of antipsychotics.

Alysicarpus vaginalis Bio-Actives as ESR Signaling Pathway Inhibitor for Breast Cancer Treatment: A Network Pharmacology Approach.

In our previous study Alysicarpus vaginalis (AV) has appeared as a promising target for breast cancer hence we have screened potential targets by in silico, In Vitro and In Vivo methods. A network pharmacology (NP) approach involves prediction and validating of targets via molecular modeling, western blotting and In Vivo MNU-induced mammary cancer. The PPI network showed the 573 edges between 214 nodes (targets) that are involved in breast cancer and important one are ESR-1, ESR-2, AR, EGFR, NOS3, MAPK, KDR, SRC and MET. Compound-target-pathway network involves 04 compounds and 221 interactive protein targets associated with breast cancer. GO and KEGG enrichment analysis predicted the ERR, c-MET, PDGFR-α/ß, EGFR, and VEGF as a key targets in the breast cancer treatment which are validated via molecular modeling. Expression of ER-α, AR and EGFR were significantly down regulated by AV in MCF-7 cell line. In addition, the immunoreactivity of ER-α was reduced significantly in MNU-induced mammary carcinoma, which is a key target in ER + breast cancer. Overall, this study scientifically light ups the pharmacological mechanism of AV in the treatment of breast cancer, strongly associated with the regulation of ESR signaling pathway.

Pyridine/Pyrimidine Substituted Imidazol-5-one Analogs as HIV-1 RT Inhibitors: Design, Synthesis, Docking and Molecular Dynamic Simulation Studies.

BACKGROUND: This paper reports the synthesis, Non-nucleoside reverse transcriptase inhibitory (NNRTIs) activity and computational studies of 2-((4-chloro-2-subtitutedphenoxy) methyl)-4-(furan-2-ylmethylene)-1-substituted Pyridine/-pyrimidine-1H-imidazol-5(4H)-ones. METHODS: The imidazol-5-one analogs were synthesized by conventional method and characterized by FT-IR, NMR and mass spectral data. All compounds were evaluated for in-vitro NNRTI activity by using reverse transcriptase (RT) assay kit (Roche). The in-silico docking studies were conducted on RT enzyme to investigate binding site interactions of synthesized compounds. The MMGBSA method was also used to calculate the binding free energy between the inhibitors and RT enzyme. The MD simulation was further performed for the apo form of the RT enzyme and docked complex of compound A6-RT enzyme to better understand the stability of the protein-ligand complex. RESULTS: The bioactivity analysis revealed that most of the synthesized compounds showed significant inhibitory activity against RT enzyme and the IC50 value was found to be in the range of 1.76-3.88 µM. The computational studies suggest that the docked compounds form the H-bonding with amino acid residue Lys101 and hydrophobic interactions with amino acid residues Tyr188, Tyr181, Trp229, and Tyr318, which act as the primary driving forces for protein-ligand interaction. CONCLUSION: The reported imidazol-5-one analogs can act as lead for further development of prospective RT inhibitors.

Benzimidazole-1,2,3-triazole hybrid molecules: synthesis and study of their interaction with G-quadruplex DNA.

A series of new benzimidazole-1,2,3-triazole hybrid derivatives have been synthesized via 'click' reaction and evaluated for their in vitro cytotoxicity as well as DNA binding affinity. MTT assay showed that all the six compounds are cytotoxic to PC3 and B16-F10 cancer cell lines. Though all the compounds showed moderate interaction with G4, c-Myc promoter DNA and dsDNA, 4f exhibited selective interaction with G-quadruplex DNA over duplex DNA as demonstrated by spectroscopic experiments like UV-vis spectroscopy, fluorescence spectroscopy, CD spectroscopy, thermal melting and fluorescence lifetime experiments. They also confirm the G-quadruplex DNA stabilizing potential of 4f. Viscosity measurements also confirm that 4f exhibits high G-quadruplex DNA selectivity over duplex DNA. Docking studies supported the spectroscopic observations. Cell cycle analysis showed that 4f induces G2/M phase arrest and induces apoptosis. Hence, from these experimental results it is evident that compound 4f may be a G-quadruplex DNA groove binding molecule with anticancer activity.

Network analysis and molecular mapping for SARS-CoV-2 to reveal drug targets and repurposing of clinically developed drugs.

Novel coronavirus (SARS-CoV-2), turned out to be a global pandemic with unstoppable morbidity and mortality rate. However, till date there is no effective treatment found against SARS-CoV-2. We report on the major in-depth molecular and docking analysis by using antiretroviral (Lopinavir and ritonavir), antimalarial (Hydroxychloroquine), antibiotics (Azithromycin), and dietary supplements (Vitamin C and E) to provide new insight into drug repurposing molecular events involved in SARS-CoV-2. We constructed three drug-target-pathways-disease networks to predict the targets and drugs interactions as well as important pathways involved in SARS-CoV-2. The results suggested that by using the combination of Lopinavir, Ritonavir along with Hydroxychloroquine and Vitamin C may turned out to be the effective line of treatment for SARS-CoV-2 as it shows the involvement of PARP-1, MAPK-8, EGFR, PRKCB, PTGS-2, and BCL-2. Gene ontology biological process analysis further confirmed multiple viral infection-related processes (P < 0.001), including viral life cycle, modulation by virus, C-C chemokine receptor activity, and platelet activation. KEGG pathway analysis involves multiple pathways (P < 0.05), including FoxO, GnRH, ErbB, Neurotrophin, Toll-like receptor, IL-17, TNF, Insulin, HIF-1, JAK-STAT, Estrogen, NF-kappa, Chemokine, VEGF, and Thyroid hormone signaling pathway in SARS-CoV-2. Docking study was carried out to predict the molecular mechanism Thus, the potential drug combinations could reduce viral infectivity, viral replication, and abnormal host inflammatory responses and may be useful for multi-target drugs against SARS-CoV-2.

A network pharmacology-based approach to explore potential targets of Caesalpinia pulcherima: an updated prototype in drug discovery.

Caesalpinia pulcherima (CP) is a traditional herb used for the treatment of asthma, bronchitis, cancer, anti-bacterial, anti-fungal and as abortifacient. In the present study, bioactive components and potential targets in the treatment of breast cancer validated through in silico, in vitro and in vivo approach. The results for the analysis were as among 29 components, only four components were found active for further study which proved the use of CP as a multi-target herb for betterment of clinical uses. The results found by PPI states that our network has significant interactions which include the ESR-1, ESR-2, ESRRA, MET, VEGF, FGF, PI3K, PDK-1, MAPK, PLK-1, NEK-2, and GRK. Compound-target network involves 4 active compound and 150 target genes which elucidate the mechanisms of drug action in breast cancer treatment. Furthermore, on the basis of the above results the important proteins were fetched for the docking study which helps in predicting the possible interaction between components and targets. The results of the western blotting showed that CP regulates ER and EGFR expression in MCF-7 cell. In addition to this animal experimentation showed that CP significantly improved immunohistological status in MNU induced carcinoma rats. Network pharmacology approach not only helps us to confirm the study of the chosen target but also gave an idea of compound-target network as well as pathways associated to the CP for treating the complex metabolic condition as breast cancer and they importance for experimental verification.

A Validated Stability-Indicating Liquid Chromatographic Method for the Determination of Lorcaserin and Related Impurities in DRUG Substance Supported by Quality by Design.

Lorcaserin (LOR) is selective and potent antiobesity drug that targets the activation of the serotonin 5HT2C receptor. Here a novel, specific, sensitive stability indicating method was developed and validated for the quantitative determination of LOR and its process-related impurities using quality by design principles. By applying experimental design, the authors examine the multifactorial effect of parameters on the critical resolution pair and generated design space representing the robust design. LOR was subjected to stress condition and found stable at all condition, only found significant degradation at oxidative stress condition. The chromatographic separation of degradation product and its process-related impurities were achieved on a Phenomenox Luna phenyl-hexyl column (150 × 4.6 mm × 5 µm), with mobile phase consisting of 10 mM ammonium formate containing 0.1% ammonia solution; pH adjusted to 2.8 with trifluoroacetic acid as solvent A and methanol/acetonitrile (5/95) as solvent B delivered with gradient program at a flow rate of 1.0 mL/min, column temperature was maintained at 25°C and analytes were monitored at 220 nm. The injection volume was 5 µL. The developed RP-LC method was validated and found linear, accurate, specific, selective, precise and robust. The structure of impurities was confirmed by direct mass analysis.

Immunomodulatory dose of clindamycin in combination with ceftriaxone improves survival and prevents organ damage in murine polymicrobial sepsis.

Sepsis is a life-threatening organ dysfunction resulting from inflammatory responses instigated by toxins secreted by bacteria. Immunomodulatory effect of clindamycin is earlier reported in a murine lipopolysaccharide (LPS)-induced sepsis model. There are no studies demonstrating the immunomodulatory effect of clindamycin in combination with ceftriaxone in a clinically relevant murine polymicrobial sepsis model induced by cecal ligation and puncture (CLP). Ceftriaxone is combined to control the bacterial growth. Following 3 h of CLP challenge, Swiss albino mice were administered vehicle, ceftriaxone alone (100 mg/kg, subcutaneously), and in combination with clindamycin at immunomodulatory dose (200 mg/kg, intraperitoneally). Survival was assessed for 5 days, and bacterial count and biochemical and physiological parameters were measured after 18 h of CLP challenge. Ceftriaxone alone caused significant reduction in bacterial count in blood, peritoneal fluid, lung, liver, and kidney homogenate which was not further substantially reduced by ceftriaxone and clindamycin combination. Day 5 survival was greatly improved by combination compared with ceftriaxone alone which was also evident through marked drop in blood glucose, total white blood cell (WBC) count, and body temperature. The combination group significantly mitigated the cytokine (tumor necrosis factor (TNF)-α and interleukin (IL)-6) and myeloperoxidase (MPO) levels in plasma, lung, liver, and kidney of CLP-challenged mice, which further helped in significantly suppressing the elevated levels of liver and kidney function parameters. Clindamycin at immunomodulatory dose in combination with ceftriaxone attenuated organ damage and improved survival of septic mice by suppressing infection, inflammatory responses, and oxidative stress.

Immunomodulatory Effect of Doxycycline Ameliorates Systemic and Pulmonary Inflammation in a Murine Polymicrobial Sepsis Model.

Acute lung injury is an inflammatory condition developed after severe sepsis in response to excessive secretion of pro-inflammatory cytokines. Doxycycline is widely reported to possess immunomodulatory activity through inhibition of various inflammatory pathways. Considering the broad spectrum of anti-inflammatory activity, protective effect of doxycycline was evaluated in clinically relevant murine polymicrobial sepsis model induced by caecal ligation and puncture (CLP). In this model, sepsis is accompanied with infection and therefore ceftriaxone at sub-protective dose was combined to retard the bacterial growth. Three hours after CLP challenge, mice were administered vehicle, ceftriaxone (100 mg/kg subcutaneously) alone and in combination with immunomodulatory dose of doxycycline (50 mg/kg, intraperitoneal) and survival were monitored for 5 days. Bacterial count in blood and peritoneal fluid along with cytokines [interleukin (IL)-6, IL-1ß, tumour necrosis factor (TNF)-α] and myeloperoxidase (MPO) in plasma and lung homogenate were measured at 18 h post-CLP. Plasma glutathione (GSH) was also determined. Doxycycline in presence of ceftriaxone improved survival of septic mice by significantly reducing the plasma and lung pro-inflammatory cytokines and MPO levels. It also increased plasma GSH levels. Doxycycline did not improve antibacterial effect of ceftriaxone in combination, suggesting that the protective effect of doxycycline was due to its immunomodulatory activity. Doxycycline in the presence of ceftriaxone demonstrated improved survival of septic mice by modulating the immune response.

Targeting Small Molecule Tyrosine Kinases by Polyphenols: New Move Towards Anti-tumor Drug Discovery.

BACKGROUND: Cancer is a complex disease involving genetic and epigenetic alteration that allows cells to escape normal homeostasis. Kinases play a crucial role in signaling pathways that regulate cell functions. Deregulation of kinases leads to a variety of pathological changes, activating cancer cell proliferation and metastases. The molecular mechanism of cancer is complex and the dysregulation of tyrosine kinases like Anaplastic Lymphoma Kinase (ALK), Bcr-Abl (Fusion gene found in patient with Chronic Myelogenous Leukemia (CML), JAK (Janus Activated Kinase), Src Family Kinases (SFKs), ALK (Anaplastic lymphoma Kinase), c-MET (Mesenchymal- Epithelial Transition), EGFR (Epidermal Growth Factor receptor), PDGFR (Platelet-Derived Growth Factor Receptor), RET (Rearranged during Transfection) and VEGFR (Vascular Endothelial Growth Factor Receptor) plays major role in the process of carcinogenesis. Recently, kinase inhibitors have overcome many problems of traditional cancer chemotherapy as they effectively separate out normal, non-cancer cells as well as rapidly multiplying cancer cells. METHODS: Electronic databases were searched to explore the small molecule tyrosine kinases by polyphenols with the help of docking study (Glide-7.6 program interfaced with Maestro-v11.3 of Schrödinger 2017) to show the binding energies of polyphenols inhibitor with different tyrosine kinases in order to differentiate between the targets. RESULTS: From the literature survey, it was observed that the number of polyphenols derived from natural sources alters the expression and signaling cascade of tyrosine kinase in various tumor models. Therefore, the development of polyphenols as a tyrosine kinase inhibitor against targeted proteins is regarded as an upcoming trend for chemoprevention. CONCLUSION: In this review, we have discussed the role of polyphenols as chemoreceptive which will help in future for the development and discovery of novel semisynthetic anticancer agents coupled with polyphenols.

Chemomodulatory effects of Alysicarpus vaginalis extract via mitochondria-dependent apoptosis and necroptosis in breast cancer.

The present study intended to assess the anticancer potential of Alysicarpus vaginalis ethyl acetate fraction (AVEAF) in breast cancer cell lines (MCF-7 and MDA-MB-453) and against N-methyl-N-nitrosourea (MNU) induced mammary carcinoma in Sprague-Dawley rats which resemble the human estrogen dependent breast cancer. The SRB assay showed that the maximum growth inhibition rate of AVEAF on MCF-7 cell was 27.12 at 100 µg/ml. Flow cytometry analysis observed that AVEAF induced the cell cycle arrest at the S phases and decreased in mitochondrial membrane potential on the MCF-7 cells. AVEAF elevated intracellular ROS level in the MCF-7 cells which were reversed with N-acetycysteine (2 mM) pretreatment indicating that AVEAF induced mitochondrial-mediated apoptosis via augmentation of intracellular ROS. Western blotting exhibited that AVEAF increased the expression of pro-apoptotic protein Bax while decreasing anti-apoptotic proteins Bcl-2 and Bcl-xL expression which promoted the cleavage of caspase-9, PARP1, RIPK 1, and RIPK 3. Additionally, AVEAF exerted anticancer effect on tumor-bearing rats and the tumor inhibition rate is 50%. Data of the study indicate that AVEAF exhibits In Vitro and In Vivo anticancer activities that associate with its ROS-mediated mitochondrial-mediated intrinsic pathway of apoptosis and necroptosis in MCF-7 cells and may serve as a potential against breast cancer.

Formulation Optimization and Biopharmaceutical Evaluation of Imatinib Mesylate Loaded ß-cyclodextrin Nanosponges.

BACKGROUND: Many researchers have prepared and evaluated nanosponges and claimed their advantages as an effective drug carrier, especially it was observed prominently in case of anti-fungal drugs. The materials employed to synthesize nanosponges were mainly crosslinking agents, different beta-cyclodextrin and other cellulose-based polymers. Many of them had used ratio proportions of cross-linking agents, d polymers to synthesize these nanosponges which ultimately produce a porous mesh-like network known as nanosponges where actually drug is encapsulated or loaded. OBJECTIVE: In the present investigation, we observed the effect of various levels of crosslinking agents and beta-cyclodextrin concentrations on porosity, drug encapsulation, zeta potential and drug release by employing the quality by design approach to synthesize nanosponges rather than merely keeping both concentrations in proportions. METHODS: We have slightly modified the method reported earlier i.e. melting method in which we have used rota evaporator receiver vessel for melting cross-linking agent and beta- cyclodextrin, rotated at 20 RPM at 100°C. RESULTS: In a quality by design approach, we observed that out of four dependent variables i.e. porosity, drug loading, zeta potential and drug release, three significantly depend on the crosslinking of beta-cyclodextrin molecules which is highly appreciated by the amount of cross-linking agent present in the reaction. The pharmacokinetics of Imatinib loaded optimized nanosponges were compared with the reference product to observe the pattern of absorption and disposition. CONCLUSION: Nanosponges synthesized by optimization technique could be effective means of anti-cancer drug oral administration as they encapsulate the drug effectively and offer a prolonged release of drug which gradually releases the drug and avoids unnecessary exposure of the drug.

Synthesis, Biological Investigation and Docking Study of Novel Chromen Derivatives as Anti-Cancer Agents.

BACKGROUND: According to the latest global cancer data, cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018. Among that female breast cancer ranks as the fifth leading cause of death (627000 deaths, 6.6%). The main causative factor involved in breast cancer development and progression is the Estrogen Receptor (ER) which is the essential target for anti-cancer drug discovery. Since millennia ER-α has been considered as an oncology mark for the treatment of breast cancer. METHODS: A series of novel 6-methyl-3-(3-oxo-1-phenyl-3-(4-(2-(piperidin-1-yl)ethoxy)phenyl)propyl)-2Hchromen- 2-one was designed, synthesized and screened for their anti-breast cancer activity against estrogen receptor-positive MCF-7, ZR-75-1 and negative MDA-MB-435 human breast cancer cell lines. Estrogen level of all the potent cytotoxic compounds were measured on day 30 of intoxication was compared with the control and N-methyl-N-nitrosourea (MNU) group. The docking study was performed to predict binding orientation towards the estrogen receptor-α. RESULTS: Among the synthesized compounds C-3, C-5 and C-15 were showing potent cytotoxicity against estrogen receptor-positive MCF-7. The potent cytotoxic compounds C-3, C-5 and C-15 were further evaluated for in vivo anti-cancer activity by MNU induced mammary carcinoma in female sprague-dawley rats. The in vivo anticancer activity result shows that the compound C-5 has protuberant affinity towards estrogen receptor as standard TAM (Tamoxifen). The docking of the synthesized chromen derivatives showed interaction modes comparable to that of the co-crystallized ligands. CONCLUSION: The designed class has very promising starting point for the development and further improvement in anti-breast cancer class of drugs.

Azithromycin in Combination with Ceftriaxone Reduces Systemic Inflammation and Provides Survival Benefit in a Murine Model of Polymicrobial Sepsis.

Sepsis is a life-threatening systemic inflammatory condition triggered as a result of an excessive host immune response to infection. In the past, immunomodulators have demonstrated a protective effect in sepsis. Azithromycin (a macrolide antibiotic) has immunomodulatory activity and was therefore evaluated in combination with ceftriaxone in a clinically relevant murine model of sepsis induced by cecal ligation and puncture (CLP). First, mice underwent CLP and 3 h later were administered the vehicle or a subprotective dose of ceftriaxone (100 mg/kg of body weight subcutaneously) alone or in combination with an immunomodulatory dose of azithromycin (100 mg/kg intraperitoneally). Survival was monitored for 5 days. In order to assess the immunomodulatory activity, parameters such as plasma and lung cytokine (interleukin-6 [IL-6], IL-1ß, tumor necrosis factor alpha) concentrations, the plasma glutathione (GSH) concentration, plasma and lung myeloperoxidase (MPO) concentrations, body temperature, blood glucose concentration, and total white blood cell count, along with the bacterial load in blood, peritoneal lavage fluid, and lung homogenate, were measured 18 h after CLP challenge. Azithromycin in the presence of ceftriaxone significantly improved the survival of CLP-challenged mice. Further, the combination attenuated the elevated levels of inflammatory cytokines and MPO in plasma and lung tissue and increased the body temperature and blood glucose and GSH concentrations, which were otherwise markedly decreased in CLP-challenged mice. Ceftriaxone produced a significant reduction in the bacterial load, while coadministration of azithromycin did not produce a further reduction. Therefore, the survival benefit offered by azithromycin was due to immunomodulation and not its antibacterial action. The findings of this study indicate that azithromycin, in conjunction with appropriate antibacterial agents, could provide clinical benefits in sepsis.

Liquid chromatographic separation and thermodynamic investigation of lorcaserin hydrochloride enantiomers on immobilized amylose-based chiral stationary phase.

A novel liquid chromatographic method was developed for enantiomeric separation of lorcaserin hydrochloride on Chiralpak IA column containing chiral stationary phase immobilized with amylose tris (3.5-dimethylphenylcarbamate) as chiral selector. Baseline separation with resolution greater than 4 was achieved using mobile phase containing mixture of n-hexane/ethanol/methanol/diethylamine (95:2.5:2.5:0.1, v/v/v/v) at a flow rate of 1.2 mL/min. The limit of detection and limit of quantification of the S-enantiomer were found to be 0.45 and 1.5 µg/mL, respectively; the developed method was validated as per ICH guideline. The influence of column oven temperatures studied in the range of 20°C to 50°C on separation was studied; from this, retention, separation, and resolution were investigated. The thermodynamic parameters ΔH°, ΔS°, and ΔG° were evaluated from van't Hoff plots,(Ink' versus 1/T) and used to explain the strength of interaction between enantiomers and immobilized amylose-based chiral stationary phase.